The invention relates to novel 2-(N-cyanoimino)thiazolidin-4-one derivatives or pharmaceutically acceptable salts or solvates thereof, which have excellent activities in a lowering blood triglyceride level and a cholesterol level, and are useful for prevention from and/or treatment of hyperlipidemia and related complications.
Many epidemiological studies have shown that hypercholesterolemia is a risk factor for coronary heart disease (CHD). Recently, hypertriglycemia is confirmed to be an independent risk factor for CHD. (J Jpn Atheroscler Soc, 25 (1-2), 1-34 (1997)xe2x80x94Guideline for Diagnosis and Treatment of Hyperlipidernias in Adults).
For the therapy of hypertriglycemia, dextran sulfate sodium, nicotinic acid derivatives, fibric acid derivatives (fibrates) have been used as the first choice. In particular bezafibrate is known to have more potent cholesterol lowering property as well as triglyceride lowering property than the earlier fibrates. And for hypercholesterolemia, HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, etc., known as statins) are generally provided for clinical use.
When blood cholesterol level alone is elevated, HMG-CoA reductase inhibitors are employed. However, when both levels of blood cholesterol and triglyceride are elevated or the effect of hypolipidemic agent is not sufficient, some lipid lowering drugs are combined.
Thus, an aim of the present invention is to provide a novel class of potent hypolipidemic agents, which reduce more effectively a blood triglyceride level or both levels of blood triglycerides and cholesterol.
Some antidiabetic agents that are partially analogous to the compounds of the present invention have been found and developed, for example, troglitazone and pioglitazone. However, they are thiazolidin-2,4-dione derivatives, and according to the conference abstract of the 28th Meeting of the Japan Atherosclerosis Society, Osaka,. June, 1996, No.024, pioglitazone did not change total cholesterol and triglyceride levels in hyperlipidemic rabbits. Therefore, from a view of chemical and biological properties, the compounds of the present invention are considered to be different from those antidiabetic compounds.
This invention provides prophylactic or therapeutic agents for hyperlipidemia and related complications comprising novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I or a pharmaceutically acceptable salt or solvate thereof as active ingredients: 
wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C1-C4 alkyl group, a haloalkyl group, a halogen atom or xe2x80x94OR5;
R1 represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C1-C4 alkylene or alkenylene group optionally substituted by a phenyl group, R6xe2x80x94X, Xxe2x80x94R6, Xxe2x80x94R6xe2x80x94X, R6xe2x80x94Xxe2x80x94R6, xe2x80x94C(xe2x95x90O)xe2x80x94NR7xe2x80x94 or xe2x80x94NR7xe2x80x94C(xe2x95x90O)xe2x80x94;
R2 and R3 are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, xe2x80x94OR8 or a halogen atom,
R4 represents a hydrogen atom or a C1-C4 alkyl group;
R5 represents a hydrogen atom or a C1-C4 alkyl group;
R6 represents a straight or branched C1-C4 alkylene or alkenylene group;
R7 represents a hydrogen atom or a C1-C4 alkyl group;
R8 represents a hydrogen atom, a C1-C4 alkyl group or an aralkyl group;
X represents an oxygen atom or a sulfur atom.
The present inventors have carried out various investigations to solve the above problem and found that the novel 2-(N-cyanoimino)thiazolidin-4-one derivatives represented by formula I have excellent blood triglyceride lowering and cholesterol lowering activities. Thus the present invention was successfully established.
xe2x80x9cSaltsxe2x80x9d refers to low toxic salts derived from sodium, potassium, ammonia or organic amines, for instance.
xe2x80x9cC1-C4 alkyl groupxe2x80x9d refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, for instance.
xe2x80x9cC1-C4 alkoxy groupxe2x80x9d refers to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert-butoxy, for instance.
xe2x80x9chalogen atomxe2x80x9d refers to generally fluorine atom, chlorine atom, bromine atom or iodine atom. More preferably it is fluorine atom or chlorine atom.
xe2x80x9cring Axe2x80x9d refers to a benzene ring, a benzodioxole ring, a benzofuran ring, a benzothiazole, a fluorene ring, an indan ring, an indoline ring or a pyridine ring, connecting with R1 at any position, for instance.
Particularly preferred compounds represented by formula I are as follows:
2-(N-Cyanoimino)-5-[(E)-4-stylylbenzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(a-methylstylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzyloxymethyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(b-methylstylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(3-phenylpropoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-chlorophenoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenylthiobenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(2-fluorostylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2,5-dimethylphenoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2-phenylpropoxy)benzylidene]thiazolidin-4-one
2-(N-Cyanoimino)-5-(3-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-benzyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(5-chlorobenzofuran-2-yl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(4-methoxystylyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(3-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(1,3-benzodioxol-5-ylmethoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-methylbenzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-chlorobenzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-methoxy-(E)-4-stylylbenzylidene]thiazolidin-4-one;,
2-(N-Cyanoimino)-5-(2-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-(benzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzylthio)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-[2-(4-chlorophenyl)ethoxy]benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[1-[(E)-4-(4-methoxystylyl)phenyl]ethylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-benzyloxy-2,5-dimethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-3-stylylbenzylidene]thiazolidin-4-one;
The compounds of the present invention are novel compounds not described in any literature and can be prepared by the following methods as the example.
A 2-(N-cyanoimino)thiazolidin-4-one represented by formula II or the salts thereof are reacted with an aldehyde or ketone represented by formula III 
wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C1-C4 alkyl group, a haloalkyl group, a halogen atom or xe2x80x94OR5;
R1 represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C1-C4 alkylene or alkenylene group optionally substituted by a phenyl group, R6xe2x80x94X, Xxe2x80x94R6, Xxe2x80x94R6xe2x80x94X, R6xe2x80x94Xxe2x80x94R6, xe2x80x94C(xe2x95x90O)xe2x80x94NR7xe2x80x94 or xe2x80x94NR7xe2x80x94C(xe2x95x90O)xe2x80x94;
R2 and R3 are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, xe2x80x94OR8 or a halogen atom;
R4 represents a hydrogen atom or a C1-C4 alkyl group;
R5 represents a hydrogen atom or a C1-C4 alkyl group;
R6 represents a straight or branched C1-C4 alkylene or alkenylene group;
R7 represents a hydrogen atom or a C1-C4 alkyl group;
R8 represents a hydrogen atom, a C1-C4 alkyl group or an aralkyl group;
X represents an oxygen atom or a sulfur atom.
The reaction can be carried out in a suitable solvent such as ethanol, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, toluene, and xylene, alternatively without employing a solvent, in the presence of ammonium acetate at a temperature ranged from ambient temperature to 200xc2x0 C., preferably from 70xc2x0 C. to 150xc2x0 C., for a period of time between 10 minutes to 10 hours, usually 20 minutes to 5 hours.
There are geometric isomers for the present compounds, however, in solution, reversible isomerization of C5-double bond of thiazolidine occurs very easily by the action of light or heat.
The compounds of the present invention have excellent activities in lowering blood triglyceride and cholesterol levels and are pharmaceutically useful as therapeutic agents for prevention and/or treatment of hyperlipidemia and related complications.
The compounds of the present invention and pharmaceutically acceptable salts thereof can be orally or parenterally administered either alone or preferably in the form of appropriate pharmaceutical compositions such as tablets, powders, granules, capsules, syrups, or injections comprised of pharmaceutically acceptable carriers, diluents, solubilizers, or other pharmaceutical additives.
The dosage will depend on the condition, age, body weight, and other factors of each patient or efficacy of an active ingredient. Generally, when the compound of the present invention is orally administered, the daily dose of the present invention preferably ranges from 10 to 400 mg for adult, and is administered once or in several divided doses a day.